PROJECT SUMMARY Influenza virus is a serious pathogen in immunocompromised persons, especially hematopoietic stem cell transplant (HSCT) recipients. However, these individuals respond poorly to trivalent inactivated influenza vaccine (TIV). High dose (HD)-TIV has increased immunogenicity and efficacy in adults >65 years of age. It is not known whether a HD-TIV will be safe and effective in severely immunocompromised persons. The standard measure of immunogenicity for TIV is hemagglutination inhibition (HAI) titers. The central hypothesis of our proposal is that HD-TIV will be more immunogenic compared to standard dose quadrivalent inactivated influenza vaccine (QIV) in pediatric HSCT recipients as evident by higher HAI antibody responses to influenza A antigens. The proposed study is a multi-center, phase II immunogenicity and safety trial comparing two doses of HD-TIV to standard dose QIV in pediatric HSCT recipients. A total of 200 pediatric patients (3-17 years of age) who received an allogeneic HSCT and are 3-35 months post-transplant will be enrolled at the following clinical sites: Vanderbilt University (lead site); Baylor School of Medicine, Texas Children's Hospital; Children's Hospital of Philadelphia; Children's Mercy Hospital; Cincinnati Children's Hospital; Nationwide Children's Hospital, Seattle Children's Hospital; St. Jude Children's Research Hospital, and UCSF Benioff Children's Hospital. The specific aims are: 1) to determine whether HD-TIV compared with standard dose QIV will increase the probability of achieving either a ?4-fold rise in HAI titer, a HAI titer ?1:40, or a higher geometric mean titer (GMT) to influenza A antigens in pediatric HSCT recipients; 2) to determine the frequency and severity of solicited local injection site adverse events and solicited systemic adverse events associated with HD-TIV compared with standard dose QIV in pediatric HSCT recipients; 3) to define the relationship between HAI titers, in vivo T and B cell phenotype, and in vitro influenza-specific T and B cell responses in pediatric HSCT recipients receiving either HD-TIV or standard dose QIV. Subjects will be randomized in a 1:1 fashion to receive either 2 doses of 2016-2017 HD- TIV (60g of each influenza antigen) or 2 doses of standard dose QIV (15g of each influenza antigen). HAI and microneutralization titers to influenza virus antigens, phenotypic B and T cell responses, B and T cell specific influenza responses, complete blood count, quantitative CD4+/CD8+/CD19+ levels, and quantitative serum IgG concentrations will be measured prior to the first and second vaccine dose, 28-42 days after the second vaccine dose, and approximately 7 months after second vaccine. Solicited adverse events will be recorded by the parent/subject seven days following vaccination and a telephone follow-up by study staff. The results of this study will fill a gap in knowledge regarding influenza vaccine responses in pediatric HSCT recipients and will guide vaccine recommendations in this vulnerable population.